Process for the preparation of 6-(perfluoroalkyl) uracil compounds form urea compounds

ABSTRACT

An improved process for the preparation of 6-(perfluoroalkyl)uracil compounds having the structural formula I                    
     from urea compounds having the structural formula II

This application claims priority from now abandoned provisionalapplication serial number 60/120,317 filed on Feb. 16, 1999.

BACKGROUND OF THE INVENTION

6-(Perfluoroalkyl)uracil compounds are useful as herbicidal agents andmethods for their preparation are known in the art.6-(Perfluoroalkyl)uracil compounds may be prepared by reacting2-(N,N-disubstituted)amino-4-(perfluoroalkyl)-1,3-oxazin-6-one compoundswith amine compounds.

Bull. Soc. Chem. Belg., 101(4), pages 313-321 (1992) discloses that2-(N,N-dialkyl)amino-4-(trifluoromethyl)-1,3-oxazin-6-one compounds areprepared by reacting ethyl 3-amino-4,4,4-trifluorocrotonate withphosgene iminium chloride compounds. However, this method is notentirely satisfactory because the required phosgene iminium chloridecompounds are difficult to handle and relatively expensive. Accordingly,a need exists in the art for an improved process for the preparation of6-(perfluoro-alkyl)uracil compounds which avoids the use of2-(N,N-disubstituted)amino-4-(perfluoroalkyl)-1,3-oxazin-6-onecompounds.

It is, therefore, an object of the present invention to provide animproved process for the preparation of 6-(perfluoroalkyl)uracilcompounds which avoids the use of2-(N,N-disubstituted)amino-4-(perfluoroalkyl)-1,3-oxazin-6-onecompounds.

Other objects and advantages of the present invention will be apparentto those skilled in the art from the description below and the appendedclaims.

SUMMARY OF THE INVENTION

The present invention provides a new process for the preparation of6-(perfluoroalkyl)uracil compounds having the structural formula I

wherein

n is an integer of 1, 2, 3, 4, 5 or 6;

Y is hydrogen or C₁-C₆alkyl; and

Q is a C₁-C₆alkyl group or an optionally substituted phenyl, benzyl,heteroaryl or methyleneheteroaryl group,

which process comprises:

(a) reacting a urea compound having the structural formula II

 wherein

Z and Z₁ are each independently C₁-C₈alkyl or Z and Z₁ may be takentogether with the atom to which they are attached to form a 4- to7-membered ring wherein ZZ₁ is represented by —(CH₂)₂O(CH₂)₂— or—(CH₂)_(m)— where m is an integer of 3, 4, 5 or 6;

Z₂ is C₁-C₆alkyl or benzyl optionally substituted on the phenyl ringwith any combination of from one to three halogen, C₁-C₄alkyl orC₁-C₄haloalkyl groups; and

n is as described above,

with an amine compound having the structural formula III

wherein Q is as described above in the presence of an acid or base toform the 6-(perfluoroalkyl)uracil compound of formula I wherein Y ishydrogen; and

(b) optionally alkylating the formula I compound wherein Y is hydrogen,to form a formula I compound wheren Y is C₁-C₆ alkyl.

DETAILED DESCRIPTION OF THE INVENTION

In a preferred embodiment of the present invention, the6-(perfluoroalkyl)uracil compounds of formula I wherein Y is hydrogenare prepared by reacting a urea compound of formula II with an aminecompound of formula III and an acid or base, preferably at a temperatureranging from about 20° C. to 150° C., in the presence of a solvent.

In another preferred embodiment of the present invention, the doublebond in the formula II compounds is predominately in the(Z)-configuration.

Advantageously, the present invention provides an improved process forthe preparation of 6-(perfluoro-alkyl)uracil compounds which avoids theuse of 2-(N,N-disubstituted)amino-4-(perfluoroalkyl)-1,3-oxazin-6-onecompounds.

The product formula I compounds may be isolated using conventionalisolation procedures such as diluting the reaction mixture with waterand separating the product or extracting the product with a suitableextraction solvent. In the isolation procedure, conventional extractionsolvents such as diethyl ether, ethyl acetate, toluene, methylenechloride, and the like, and mixtures thereof may be utilized.

Acids suitable for use in this invention include organic acidsincluding, but not limited to, C₁-C₆alkanoic acids such as formic acid,acetic acid, propionic acid and the like; and mineral acids including,but not limited to, hydrochloric acid, sulfuric acid, phosphoric acidand the like. A preferred acid is acetic acid.

Bases suitable for use in the process of the present invention include,but are not limited to, tri(C₁-C₆-alkyl)amines such as trimethylamine,triethylamine, tripropylamine, tributylamine, diisopropylethylamine andthe like; heterocyclic tertiary amines such as1,8-diaza-bicyclo[5.4.0]undec-7-ene (DBU),1,5-diazabicyclo-[4.3.0]non-5-ene (DBN), 1,4-diazabicyclo[2.2.2]octane,pyridine, substituted pyridines, quinoline, substituted quinolines andthe like; and alkali metal C₁-C₆alkoxides such as potassiumtert-butoxide, sodium tert-butoxide and the like. Preferred basesinclude 1,8-diazabicyclo-[5.4.0]undec-7-ene and1,5-diazabicyclo[4.3.0]non-5-ene.

Solvents suitable for use in step (a) of the process of this inventioninclude, but are not limited to, carboxylic acid amides such asN,N-dimethylformamide, N,N-dimethylacetamide and the like; dialkylsulfoxides such as dimethyl sulfoxide and the like; aromatichydrocarbons such as toluene, benzene, xylenes, mesitylene and the like;halogenated aromatic hydrocarbons such as chlorobenzene, fluorobenzeneand the like; aliphatic hydrocarbons such as pentane, hexane, heptaneand the like; halogenated aliphatic hydrocarbons such as methylenechloride, chloroform, carbon tetrachloride, 1,2-dichloroethane and thelike; alcohols such as methanol, ethanol, n-propanol, sec-propanol andthe like; alkanoic acids such as formic acid, acetic acid, propionicacid and the like; ketones such as acetone, methyl ethyl ketone and thelike; ethers such as diethyl ether, tetrahydrofuran, dioxane,1,2-dimethoxyethane and the like; nitrites such as acetonitrile,propionitrile and the like; and water; and mixtures thereof. It shouldbe understood that a solvent should be chosen which does not adverselyreact with the acid or base. In particular, an alkanoic acid generallywould not be a suitable solvent when a base is used.

Alkylation procedures suitable for use in this invention includeconventional procedures known in the art. In a preferred embodiment ofthis invention, the step (b) alkylation procedure comprises reacting theformula I compound wherein Y is hydrogen with an alkyl halide having thestructural formula IV or a dialkylsulfate ester having the structuralformula V

wherein X is chlorine, bromine or iodine, and Y is C₁-C₆alkyl in thepresence of a base.

Bases suitable for use in the alkylation procedures of this inventioninclude conventional bases known in the art including, but not limitedto, alkali metal hydrides such as sodium hydride and the like; alkalimetal C₁-C₆alkoxides such as potassium tert-butoxide, sodiumtert-butoxide and the like; alkali metal hydroxides such as potassiumhydroxide, sodium hydroxide and the like; alkali metal carbonates suchas sodium carbonate, potassium carbonate and the like; alkaline earthmetal hydroxides such as calcium hydroxide and the like; and alkalineearth metal carbonates such as calcium carbonate and the like.

Preferred formula II compounds for use in the process of this inventionare those wherein

Z and Z₁ are each independently C₁-C₆alkyl;

Z₂ is C₁-C₄alkyl; and

n is 1.

More preferred urea compounds of formula II for use in the process ofthe present invention are those wherein

Z and Z₁ are the same and represent methyl or ethyl;

Z₂ is methyl or ethyl; and

n is 1.

Preferred formula I compounds which may be prepared by the process ofthe present invention are those wherein

n is 1;

Y is hydrogen or C₁-C₄alkyl;

Q is

G is CH₂ or a bond;

G₁ is CX₅ or N;

G₂ is CX₄ or N;

X₁ is hydrogen, halogen or a C₁-C₆alkyl group optionally substitutedwith one epoxy group,

X₂ is hydrogen, halogen NRR₁, CO₂R₂, C(O)R₃, OR₄, SO₂R₅, SO₂NR₆R₇, C(R₈)(OR₉)₂, C(R₁₀)═NOR₁₁, C(R₁₂)═C(R₁₃)—C(OR₁₄)═NOR₁₅, CH₂O—NCO₂R₁₆,

 1,3-dioxolane optionally substituted with one C₁-C₆alkoxy group or oneor two C₁-C₄alkyl groups,

 1,3-dioxolinone optionally substituted with one C₁-C₆alkoxy group orone or two C₁-C₄alkyl groups, or

 C₁-C₄alkyl optionally substituted with one CO₂R₂ group and one halogenatom, and

X₃ is hydrogen, halogen, C₁-C₄haloalkyl, CO₂R₁₇, cyano, C₁-C₄haloalkoxy,OR₁₈ or C₁-C₄alkyl, or

when X₁ and X₂ are taken together with the atoms to which they areattached, they may form a five- or six-membered ring wherein X₁X₂ orX₂X₁ is represented by:

 —OC(R₂₀) (R₂₁)O—, —CH₂S(O)_(p)N(R₂₂)—, —SC(R₂₃)═N—, —CH═CH—CH(R₁₁)O—,—OC(O)N—, —SC(R₂₄)═N—, —ON(R₂₅)C(O)—, —OC(CO₂R₂₆)═C(R₂₇)—,—NC(R₂₈)═C(SR₂₉)—, —CH═C(CO₂R₃₀)O—, —CH₂CH(R₃₁)O— or —OC(R₃₂)(R₃₃)C(O)—, or

when X₂ and X₃ are taken together with the atoms to which they areattached, they may form a five- or six-membered ring wherein X₂X₃ orX₃X₂ is represented by:

 —NC(R₃₄)═NC(S)—, —N(R₃₅)N═C(R₃₆)—, —N(R₃₇)C(R₃₈)═N—, —N(R₃₈)C(O)CH₂O—,—N(R₃₉)C(O)CH═CH—, —S—N═C(R₄₀)—, —O—N═C(R₄₁)—, —N═N—N(R₄₂)—, —C(R₄₃)(R₄₄)C(O)N(R₄₅)— or —N(R₄₆)C(O)C(R₄₇) (R₄₈)—;

X₄ is hydrogen, halogen or OR₁₉;

X₅ is hydrogen or halogen;

R, R₅₆, R₆₄, R₆₉, R₇₀, R₇₇ and R₉₁ are each independently hydrogen,SO₂R₄₉, C₁-C₄alkyl, C₃-C₇cycloalkyl, C₃-C₆alkenyl, C₃-C₆alkynyl, phenylor benzyl;

R₁ is hydrogen, SO₂R₅₀, C(O)R₅₁, amino or C₁-C₄alkyl optionallysubstituted with CO₂R₅₂ or C(O)R₅₃;

R₂, R₁₆, R₁₇, R₂₆, R₃₀, R₆₈, R₇₅, R₇₆, R₈₂ and R₈₈ are eachindependently hydrogen, C₁-C₈haloalkyl, C₃-C₈alkenyl, C₃-C₆alkynyl,phenyl, benzyl, furfuryl, pyridyl, thienyl,

 C₁-C₈alkyl optionally substituted with CO₂R₅₄, morpholine or C(O)R₅₅,or

 an alkali metal, an alkaline earth metal, ammonium or organic ammoniumcation;

R₃, R₆₆, R₆₇, R₈₁, R₈₅ and R₈₉ are each independently hydrogen,C₁-C₆alkyl, C₃-C₆alkenyl, C₃-C₆alkynyl, NR₅₆R₅₇, phenyl or benzyl;

R₄, R₁₈, R₁₉ and R₆₅ are each independently hydrogen, C₁-C₆alkyl,C₃-C₆alkenyl, C₃-C₆alkynyl, C₁-C₄haloalkyl, C(O)R₅₆, C(S)R₅₉ or benzyl;

R₅ and R₇₂ are each independently C₁-C₆alkyl, C₁-C₆haloalkyl, NR₆₀R₆₁,imidazole or indazole;

R₆, R₁₁, R₁₂, R₁₄, R₁₅, R₂₀, R₂₁, R₂₂, R₂₅, R₂₈, R₂₉, R₃₁, R₃₂, R₃₃,R₃₅, R₄₅, R₄₆, R₆₃ and R₈₀ are each independently hydrogen orC₁-C₄alkyl;

R₇ is hydrogen, C₃-C₆alkenyl, C₃-C₆alkynyl, benzyl, or C₁-C₄alkyloptionally substituted with cyano or C(O)R₆₂;

R₈ and R₂₇ are each independently hydrogen, C₁-C₄alkyl or C₁-C₄alkoxy;

R₉ and R₉₀ are each independently C₁-C₆alkyl;

R₁₀ is hydrogen, C₁-C₆alkyl, phenyl or benzyl;

R₁₃, R₂₄ and R₃₆ are each independently hydrogen, C₁-C₆alkyl or halogen;

R₂₃ is hydrogen or NR₆₃R₆₄;

R₃₄ is hydrogen, C₁-C₄alkyl or C₁-C₄haloalkyl;

R₃₇ is hydrogen, C₁-C₄alkyl or C₂-C₈alkoxyalkyl;

R₃₈ and R₃₉ are each independently hydrogen, C₁-C₄alkyl, C₁-C₄haloalkyl,C₃-C₆alkenyl or C₃-C₆alkynyl;

R₄₀, R₄₁ and R₄₂ are each independently hydrogen, halogen, cyano, OR₆₅,C(O)R₆₆, C(S)R₆₇, CO₂R₆₈, C(═NOR₆₉),

 a C₁-C₈alkyl, C₃-C₇cycloalkyl, C₂-C₈alkenyl or C₂-C₈alkynyl group,wherein each group is optionally substituted with any combination of oneto six halogen atoms, one to three C₁-C₁₀-alkoxy groups, one or twoC₁-C₆haloalkoxy groups, one or two NR₇₀R₇₁ groups, one or twoS(O)_(q)R₇₂ groups, one or two cyano groups, one or two C₃-C₇cycloalkylgroups, one OSO₂R₇₃ group, one or two C(O)R₇₄ groups, one or two CO₂R₇₅groups, one or two C(O)SR₇₆ groups, one or two C(O)NR₇₇R₇₈ groups, oneto three OR₇₉ groups, one or two P(O) (OR₈₀)₂ groups, one 1,3-dioxolaneoptionally substituted with one to three C₁-C₄alkyl groups, or one1,3-dioxane optionally substituted with one to three C₁-C₄alkyl groups,or

 phenyl or benzyl optionally substituted with any combination of one tothree halogen atoms, one to three C₁-C₆alkyl groups, one to threeC₁-C₆alkoxy groups, one C₃-C₇cycloalkyl group, one C₁-C₄haloalkyl group,one C₁-C₄alkylthio group, one cyano group, one nitro group, one C(O)R₈₁group, one CO₂R₈₂ group, one OR₈₃ group, one SR₈₄ group, oneC₁-C₆alkoxymethyl group, one hydroxymethyl group, oneC₃-C₈alkenyloxymethyl group, or one C₁-C₈haloalkoxymethyl group;

R₄₃, R₄₄, R₄₇ and R₄₈ are each independently hydrogen, C₁-C₄alkyl,C₁-C₄haloalkyl, C₃-C₆alkenyl, C₃-C₆alkynyl or C₃-C₇cycloalkyl, or R₄₃and R₄₄ or R₄₇ and R₄₈ may be taken together with the atom to which theyare attached to form a C₃-C₇cycloalkyl group;

R₄₉, R₅₀ and R₈₆ are each independently C₁-C₆alkyl, NR₉₃R₉₄,C₁-C₄haloalkyl, C₃-C₆alkenyl, C₃-C₆alkynyl or benzyl;

R₅₁, R₅₂, R₅₃, R₅₄, R₅₅, R₅₇, R₅₈, R₅₉, R₆₀, R₆₁, R₆₂, R₇₁, R₇₃, R₇₄,R₇₈, R₈₇ and R₉₂ are each independently hydrogen, C₁-C₆alkyl,C₃-C₇cycloalkyl, C₁-C₆haloalkyl, C₃-C₆alkenyl, C₃-C₆alkynyl, phenyl orbenzyl;

R₇₉, R₈₃ and R₈₄ are each independently hydrogen, C(O)R₈₅, SO₂R₈₆,C₁-C₆haloalkyl, C₂-C₆alkenyl, C₅-C₈cycloalkenyl, C₂-C₆alkynyl, phenyl,benzyl, or C₁-C₁₀alkyl optionally substituted with one hydroxyl,benzyloxy, OC(O)R₈₇, C₁-C₆alkoxy, CO₂R₈₈, C(O)R₈₉, C(OR₉₀)₂, C(O)NR₉₁R₉₂or cyano group;

R₉₃ and R₉₄ are each independently hydrogen, C₁-C₄haloalkyl,C₂-C₆alkenyl, C₃-C₈cycloalkyl, C₁-C₈alkyl optionally substituted withone or two C₁-C₄alkoxy groups or one cyanoalkyl group, or

 benzyl or phenyl optionally substituted with any combination of one tothree halogen atoms, one to three C₁-C₄alkyl groups, one to threeC₁-C₄haloalkyl groups, one to three C₁-C₄alkoxy groups, one to threeC₁-C₄haloalkoxy groups, one cyano group or one nitro group, and

 when R₉₃ and R₉₄ are taken together with the atom to which they areattached, they form a 5- to 12-membered monocyclic or fused bicyclic,heterocyclic ring optionally substituted with one or more groupsindependently selected from halogen, cyano, nitro, amino, hydroxyl,C₁-C₄alkyl, C₁-C₄haloalkyl, C₁-C₄alkoxy, C₁-C₄haloalkoxy andC₁-C₄haloalkylsulfonyl groups; and

p and q are each independently 0, 1 or 2; and

the optical isomers, diastereomers and/or tautomers thereof.

More preferred formula I herbicidal agents which may be prepared by theprocess of this invention are those

wherein

n is 1;

Y is hydrogen or methyl;

Q is

G is CH₂ or a bond;

G₁ is CX₅ or N;

G₂ i s CX₄ or N;

X₁ is hydrogen, fluorine or C₁-C₃alkyl optionally substituted with oneepoxy group;

X₂ is hydrogen, halogen NRR₁, CO₂R₂, C(O)R₃, OR₄, SO₂R₅, SO₂NR₆R₇, C(R₈)(OR₉)₂, C(R₁₀)═NOR₁₁, C(R₁₂)═C(R₁₃)—C(OR₁₄)═NOR₁₅, CH₂O—NCO₂R₁₆,

 1,3-dioxolane optionally substituted with one C₁-C₆alkoxy group or oneor two C₁-C₄alkyl groups,

 1,3-dioxolinone optionally substituted with one C₁-C₆alkoxy group orone or two C₁-C₄alkyl groups, or

 C₁-C₄alkyl optionally substituted with one CO₂R₂ group and one halogenatom, and

X₃ is hydrogen, halogen, C₁-C₄haloalkyl, CO₂R₁₇, cyano, C₁-C₄haloalkoxy,OR₁₈ or C₁-C₄alkyl, or

when X₁ and X₂ are taken together with the atoms to which they areattached, they may form a five- or six-membered ring wherein X₁X₂ orX₂X₁ is represented by: —OC(R₂₀) (R₂₁)O—, —CH₂S(O)_(p)N(R₂₂)—,—SC(R₂₃)═N—, —CH═CH—CH(R₁₁)O—, —OC(O)N—, —SC(R₂₄)═N—, —ON(R₂₅)C(O)—,—OC(CO₂R₂₆)═CH—, —NC(R₂₈)═C(SR₂₉)—, —CH═C(CO₂R₃₀)O—, —CH₂CH(R₃₁)O— or—OC(R₃₂) (R₃₃)C(O)—, or

when X₂ and X₃ are taken together with the atoms to which they areattached, they may form a five- or six-membered ring wherein X₂X₃ orX₃X₂ is represented by: —NC(R₃₄)═NC(S)—, —N(R₃₅)N═C(R₃₆)—,—N(R₃₇)C(R₃₈)═N—, —N(R₃₈)C(O)CH₂O—, —N(R₃₉)C(O)CH═CH—, —S—N═C(R₄₀)—,—N═C(R₄₁)—, —N═N—N(R₄₂)—, —C(R₄₃) (R₄₄)C(O)N(R₄₅)— or —N(R₄₆)C(O)C(R₄₇)(R₄₈)—;

X₄ is hydrogen, halogen or OR₁₉;

X₅ is hydrogen or halogen;

R, R₆₄, R₆₉ and R₇₇ are each independently hydrogen, SO₂R₄₉ orC₁-C₄alkyl;

R₁ is hydrogen, SO₂R₅₀, C(O)R₅₁, amino or C₁-C₄alkyl optionallysubstituted with CO₂R₅₂ or C(O)R₅₃;

R₂, R₁₆, R₁₇, R₂₆, R₃₀, R₆₈, R₇₅, R₇₆, R₈₂ and R₈₈ are eachindependently hydrogen, C₃-C₆alkenyl or C₁-C₄alkyl optionallysubstituted with CO₂R₅₄, morpholine or C(O)R₅₅;

R₃, R₆₆, R₆₇, R₈₅ and R₈₉ are each independently hydrogen, C₁-C₄alkyl orNR₅₆R₅₇;

R₄, R₁₈ and R₁₉ are each independently hydrogen, C₁-C₄alkyl,C₁-C₄haloalkyl, C(O)R₅₈, C₃-C₄alkenyl or C₃-C₄alkynyl;

R₅₆ is SO₂R₄₉;

R₅₇ is hydrogen or C₁-C₄alkyl;

R₅ and R₇₂ are each independently NR₆₀R₆₁ or indazole; R₆, R₁₁, R₁₂,R₁₄, R₁₅, R₂₀, R₂₁, R₂₂, R₂₅, R₂₈, R₂₉, R₃₁, R₃₂, R₃₃, R₃₅, R₄₅, R₄₆ andR₈₀ are each independently hydrogen or methyl;

R₇ is C₁-C₄alkyl optionally substituted with cyano or C(O)R₆₂;

R₈ is hydrogen or C₁-C₄alkoxy;

R₉ and R₉₀ are each independently C₁-C₄alkyl;

R₁₀ is hydrogen or C₁-C₃alkyl;

R₁₃, R₂₄ and R₃₆ are each independently hydrogen or chlorine;

R₂₃ is NR₆₃R₆₄;

R₃₄ is C₁-C₃haloalkyl;

R₃₇ is C₂-C₄alkoxyalkyl;

R₃₈ and R₃₉ are each independently C₁-C₃haloalkyl, C₁-C₃alkyl orpropargyl;

R₄₀, R₄₁, and R₄₂ are each independently hydrogen, C(O)R₆₆, C(S)R₆₇,CO₂R₆₈, C(═NOR₆₉), C₁-C₃alkyl optionally substituted with anycombination of one or two halogen atoms, one or two C₁-C₃alkoxy groups,one or two C₁-C₃haloalkoxy group, one SO₂R₇₂ group, one or two cyanogroups, one C₃-C₅cycloalkyl group, one OSO₂R₇₃ group, one C(O)R₇₄ group,one CO₂R₇₅ group, one C(O)SR₇₆ group, one C(O)NR₇₇R₇₈ group, one to twoOR₇₉ groups, one P(O) (OR₈₀)₂ group, one 1,3-dioxolane group or one1,3-dioxane group, or

 phenyl optionally substituted with any combination of one halogen atom,one or two methyl groups, one methoxy group, one halomethyl group or oneOR₈₃ group;

R₄₃, R₄₄, R₄₇ and R₄₈ are each independently hydrogen or methyl, or R₄₃and R₄₄ or R₄₇ and R₄₈ may be taken together with the atom to which theyare attached to form a cyclopropyl group;

R₄₉, R₅₀ and R₈₆ are each independently C₁-C₄alkyl or NR₉₃R₉₄;

R₅₁R₅₂, R₅₃, R₅₄, R₅₅, R₅₈, R₆₀, R₆₁, R₆₂, R₇₃, R₇₄, R₇₈ are

 each independently hydrogen, C₁-C₄alkyl or C₁-C₄haloalkyl;

R₇₉ and R₈₃ are each independently hydrogen, C(O)R₈₅, SO₂R₈₆,C₁-C₄haloalkyl, C₃-C₄alkenyl or C₁-C₃alkyl substituted with oneOC(O)R₈₇, CO₂R₈₈, C(O)R₈₉, C(OR₉₀)₂ or cyano group;

R₉₃ and R₉₄ are each independently hydrogen or C₁-C₈alkyl; and

p is 0, 1 or 2.

The process of the present invention is especially useful for thepreparation of 6-(trifluoromethyl)uracil compounds having the structuralformula VI

wherein

Y is hydrogen or methyl;

X₅ is hydrogen or halogen;

R₄₀ is hydrogen, C(O)R₆₆, C(S)R₆₇, CO₂R₆₈,

 C₁-C₃alkyl optionally substituted with any combination of one or twohalogen atoms, one or two C₁-C₃alkoxy groups, one or two C₁-C₃haloalkoxygroups, one SO₂R₇₂ group, one or two cyano groups, one C₃-C₅cycloalkylgroup, one OSO₂R₇₃ group, one or two OR₇₉ groups, one P(O) (OR₈₀)₂group, one 1,3-dioxolane group or one 1,3-dioxane group, or

 phenyl optionally substituted with any combination of one halogen atom,one or two methyl groups, one methoxy group, one halomethyl group or oneOR₈₃ group;

R₆₆, R₆₇, R₈₅ and R₈₉ are each independently hydrogen, C₁-C₄alkyl orNR₅₆R₅₇;

R₅₆ is SO₂R₄₉;

R₅₇ is hydrogen or C₁-C₄alkyl;

R₄₉ and R₈₆ are each independently C₁-C₄alkyl or NR₉₃R₉₄;

R₉₃ and R₉₄ are each independently hydrogen or C₁-C₈alkyl;

R₆₈ and R₈₈ are each independently hydrogen, C₃-C₆alkenyl or C₁-C₄alkyloptionally substituted with CO₂R₅₄, morpholine or C(O)R₅₅;

R₅₄, R₅₅, R₆₀, R₆₁, R₇₃ and R₈₇ are each independently hydrogen,C₁-C₄alkyl or C₁-C₄haloalkyl;

R₇₂ is NR₆₀R₆₁ or indazole;

R₇₉ and R₈₃ are each independently hydrogen C(O)R₈₅, SO₂R₈₆,C₁-C₄haloalkyl, C₃-C₄alkenyl or C₁-C₃alkyl substituted with oneOC(O)R₈₇, CO₂R₈₈, C(O)R₈₉, C(OR₉₀)₂ or cyano group;

R₈₀ is hydrogen or methyl; and

R₉₀ is C₁-C₄alkyl.

Exemplary of halogen hereinabove are fluorine, chlorine, bromine andiodine. The terms “halomethyl”, “C₁-C₄haloalkyl”, “C₁-C₈haloalkyl”,“C₁-C₃haloalkoxy”, “C₁-C₄haloalkoxy” and “C₁-C₈haloalkoxymethyl” aredefined as a methyl, C₁-C₄alkyl, C₁-C₈alkyl, C₁-C₃alkoxy, C₁-C₄alkoxy orC₁-C₈alkoxymethyl group substituted with one or more halogen atoms. Informula I above, alkali metals include sodium, potassium and lithium,and alkaline earth metals include calcium and magnesium. Organicammonium cations suitable for use in the present invention include, butare not limited to, a group consisting of a positively charged nitrogenatom joined to from one to four aliphatic groups, each containing fromone to sixteen carbon atoms.

In formula I above, 5- to 12-membered monocyclic or fused bicyclic,heterocyclic rings include, but are not limited to, benzimidazole,imidazole, imidazoline-2-thione, indole, isatoic anhydride, morpholine,piperazine, piperidine, purine, pyrazole, pyrrole, pyrrolidine and1,2,4-triazole rings wherein each ring is optionally substituted withone or more groups independently selected from halogen, cyano, nitro,amino, hydroxyl, C₁-C₄alkyl, C₁-C₄haloalkyl, C₁-C₄alkoxy,C₁-C₄haloalkoxy, or C₁-C₄haloalkylsulfonyl groups.

Starting formula II urea compounds may be prepared by reacting aβ-amino-β-(perfluoroalkyl)acrylate compound having the structuralformula VII

wherein n and Z₂ are as described hereinabove with a base and acarbamoyl chloride compound having the structural formula VIII

wherein Z and Z₁ are as described hereinabove.

Formula VII β-amino-β-(perfluoroalkyl)acrylate compounds are known inthe art and may be prepared according to the procedures described inU.S. Pat. No. 5,777,154; Journal of Heterocyclic Chemistry, 9, pages513-522 (1972); and Institute of Chemistry, Urals Scientific Center,Academy of Sciences of the USSR, Sverdlovsk, pages 1442-1447(1987)—English translation of Zhurnal Organicheskoi Khimii, 22(8), pages1603-1609 (1986).

Carbamoyl chloride compounds of formula VIII are known in the art andmay be prepared by conventional procedures. In addition, certain formulaVIII carbamoyl chloride compounds are commercially available.

Amine compounds having the structural formula IIIa

wherein X₁, X₅ and R₄₀ are as described hereinabove, may be prepared, asshown in Flow Diagram I, by cyclizing a ketone of formula IX with sulfurand ammonium hydroxide or ammonia to form a nitrobenzisothiazole offormula X, and reducing the formula X compound using conventionalreducing agents such as iron in acetic acid.

FLOW DIAGRAM I

Starting amine compounds having the structural formula IIIb

wherein X₁, X₅ and R₄₁ are as described hereinabove, may be prepared, asillustrated in Flow Diagram II, by reacting a ketone of formula XI withhydroxylamine hydrochloride optionally in the presence of sodium acetateto form an oxime of formula XII, cyclizing the formula XII compound witha base such as potassium hydroxide to form a nitrobenzisoxazole offormula XIII, and reducing the formula XIII compound using conventionalreducing agents such as tin(II) chloride in acetic acid.

FLOW DIAGRAM II

Alternatively, formula XIII nitrobenzisoxazole compounds may beprepared, as shown in Flow Diagram III, by reacting a ketone of formulaXIV with hydroxylamine hydrochloride optionally in the presence of abase such as sodium acetate to form an oxime of formula XV, cyclizingthe formula XV compound with 1,1′-carbonyl-diimidazole in the presenceof a base such as tri-ethylamine to form a benzisoxazole of formula XVI,and nitrating the formula XVI compound using conventional methods suchas a nitric acid/sulfuric acid mixture.

FLOW DIAGRAM III

Intermediate compounds of formulas X and XIII wherein R₄₀ and R₄₁ areOR₆₅ may be prepared, as shown in Flow Diagram IV, by nitrating abenzisoxazol-3-ol or benzisothiazol-3-ol of formula XVII with aconventional nitrating agent such as a nitric acid/sulfuric acid mixtureto form a 5-nitrobenzisoxazol-3-ol or 5-nitrobenzisothiazol-3-ol offormula XVIII, and reacting the formula XVIII compound with anelectrophile of formula XIX in the presence of a base such as potassiumcarbonate.

FLOW DIAGRAM IV

Formula X and XIII intermediate compounds wherein R₄₀ and R₄₁ are Cl orBr may be prepared, as shown in Flow Diagram V, by reacting a5-nitrobenzisoxazol-3-ol or 5-nitrobenzisothiazol-3-ol of formula XVIIIwith phosphorous oxychloride, phosphorous oxybromide or phosphorouspentabromide.

FLOW DIAGRAM V

Other methods for the preparation of formula IIIa and IIIb aminecompounds will become apparent from the examples set forth below. Inaddition, certain compounds of formulas IIIa, IIIb, X and XIII may beconverted into other compounds of formulas IIIa, IIIb, X and XIII byusing conventional procedures known to those skilled in the art.

Other formula III amine compounds are known in the art and may beprepared according to the procedures described in EP 561319-A; EP540023-A; EP 545206-A; EP 542685-A; EP 473551-A; EP 476697-A; EP489480-A; EP 496595-A; EP 420194-A; EP 648749-A; EP 705829-A; EP714602-A; JP 9241245; JP 9301973; U.S. Pat. No. 5,169,430; U.S. Pat. No.5,310,723; U.S. Pat. No. 5,324,854; U.S. Pat. No. 5,391,541; U.S. Pat.No. 5,399,543; U.S. Pat. No. 5,484,763; U.S. Pat. No. 5,523,278; U.S.Pat. No. 5,602,077; U.S. Pat. No. 5,661,108; WO 93/14073; WO 94/10155;WO 94/24128; WO 91/07393; WO 91/107392; WO 95/04461; WO 95/05079; WO95/05080; WO 95/17096; WO 95/25725; WO 95/29168; WO 95/32952; WO95/33746; WO 96/02518; WO 96/08151; WO 96/14315; WO 96/28442; WO96/34859; WO 96/35679; WO 97/01541; WO 97/01542; WO 97/05118; WO97/07105; WO 97/08170; WO 97/08171; WO 97/08953; WO 97/12884; WO97/12886; WO 97/29094; WO 97/29105; WO 97/34484; WO 97/35845; WO97/42176; WO 97/42188; WO 97/45418; WO 97/47607; WO 98/02422; WO98/06706; WO 98/08824; WO 98/27057; WO 98/27067; WO 98/27082; and WO98/27088, among others.

In order to facilitate a further understanding of this invention, thefollowing examples are presented primarily for the purpose ofillustrating more specific details thereof. The scope of the inventionshould not be deemed limited by the examples but encompasses the entiresubject matter defined in the claims.

EXAMPLE 1 Preparation of Ethyl 3-[(N,N-dimethylcarbamoyl)amino]-4,4,4-trifluorocrotonate, (Z)—

Ethyl 3-amino-4,4,4-trifluorocrotonate (18.4 g, 100 mmol) is added to astirred solution of sodium hydride (60% in mineral oil, 9.6 g, 250 mmol)in N,N-dimethyl-formamide (60 mL) at 5° C. under nitrogen over a 60minute period. The reaction mixture is allowed to warm to and held atroom temperature for 15 minutes, cooled to 5° C., and treated withdimethylcarbamoylchloride (21.6 g, 200 mmol) over a 60 minute period.The resultant solution is then warmed to and held at room temperaturefor 2 hours, diluted with water (150 mL), and extracted with ethylacetate (2×150 mL). The combined organic layers are dried, filtered andconcentrated, and the mineral oil layer is removed to obtain a residue.Flash column chromatography of the residue on silica gel using a 85:15hexanes/ethyl acetate solution gives the title product as a yellowliquid (18.1 g, 71% yield): ¹H NMR (DMSO-d₆)δ 9.18 (s,1H), 5.85 (s, 1H),4.20 (q, 2H), 2.89 (s, 6H), 1.18 (t, 3H) ; ¹⁹F NMR δ −65.7 (s).

Using essentially the same procedure, the following compounds areobtained:

(Z) - configuration Z Z₁ Z₂ mp (° C.) Yield (%) C₂H₅ C₂H₅ C₂H₅ yellowoil 88 —(CH₂)₄— C₂H₅ 54-57 37 CH₃ CH₃ CH₃ C₂H₅ C₂H₅ CH₃ —(CH₂)₄— CH₃

EXAMPLE 2 Preparation of3-(3-Methyl-1,2-benzoisothiazol-5)-6-(trifluoromethyl)-2,4(1H,4H)-pyrimidinedione

A solution of ethyl3-[(N,N-dimethylcarbamoyl)-amino]-4,4,4-trifluorocrotonate, (Z)— (1.15g. 4.5 mmol) and 5-amino-3-methyl-1,2-benzoisothiazole (0.75 g, 4.5mmol) in glacial acetic acid (7 mL) is held at gentle reflux for 1 hour,cooled, and diluted with water. The resultant aqueous mixture isfiltered to obtain a solid. The solid is washed with water and dried togive the title product (1.3 g, 88% yield) which is identified by ¹H and¹⁹F NMR spectral analyses.

Following essentially the same procedure, but using the appropriatereagents, the following compounds are obtained:

Z Z₁ Q Acid/Base Solvent Color/State/mp (° C.) Yield (%) CH₃ CH₃

CH₃CO₂H CH₃CO₂H >250 88 C₂H₅ C₂H₅

CH₃CO₂H CH₃CO₂H white solid 92 C₂H₅ C₂H₅

CH₃CO₂H CH₃CO₂H brown solid 74 C₂H₅ C₂H₅

DBU¹ xylene orange solid 13 C₂H₅ C₂H₅

CH₃CO₂H toluene red solid 87 C₂H₅ C₂H₅

CH₃CO₂H toluene yellow solid 63 —(CH₂)₄—

CH₃CO₂H CH₃CO₂H pink solid 89 ¹1,8-Diazabicyclo[5.4.0]undec-7-ene

EXAMPLE 3 Preparation of2′-Chloro-2-methoxy-5-methyl-5′-nitrobenzophenone

A mixture of aluminum chloride (33.3 g, 25.0 mmol) in methylene chlorideis cooled to about 5° C., treated over one hour with p-methylanisole(31.6 g, 25.0 mmol) while maintaining the reaction mixture temperaturebelow 10° C., treated over 20 minutes with a solution of2-chloro-5-nitrobenzoyl chloride (50.0 g, 22.7 mmol) in methylenechloride while maintaining the reaction mixture temperature below 10°C., warmed to and stirred at room temperature for 60 minutes, and pouredonto ice. The resultant aqueous mixture is treated with concentratedhydrochloric acid (50 mL) and extracted with methylene chloride. Theorganic extract is dried over anhydrous magnesium sulfate andconcentrated in vacuo to give a yellow solid. After placing the solid ina Kugelrohr apparatus at 40° C. to remove residual p-methylanisole, thetitle product is obtained as a beige solid (68.8 g, 99.1%) which isidentified by NMR spectral analyses.

Using essentially the same procedure, the following compounds areobtained:

X₃ X₅ W W₁ W₂ W₃ W₄ mp ° C. Cl H Cl H H I H H OCH₃   115-116.5 Cl H H HCH₃ H OCH₃ Cl H H H C₂H₅ H H Cl H H CH₃ CH₃ H OCH₃ Cl H H H OCH₃ H H108-112 Cl H H C₂H₅ H H OCH₃   98-99.5 Cl H H H OCH₃ H CH₃ 91-92 Cl H HH CH₃ H H 95.5-96.5 Cl H H H SCH₃ H H 127-128 Cl H H H CH₃ H OCH₃  91-92.5 Cl H H H C₂H₅ H H Cl H H H Cl H H 88.5-90.5 Cl H H H F H H  68-69.5 Cl H H Cl H H OCH₃ 124-126 Cl H H OCH₃ H H OCH₃ 71-73 Cl H H HOCH₃ H OCH₃  98-100 Cl H H CH₃ CH₃ H OCH₃ 127-129 Cl H H H Cl H OCH₃96-99 Cl H CH₃ H CH₃ H OCH₃ 108.5-110   Cl H H H H CH₃ OCH₃ 71-74 Cl H HH N(CH₃)SO₂CH₃ H H Cl H H CH₃ Cl H OCH₃ 126-128 Cl H H CH₃ H CH₃ OCH₃110-112 Cl H CH₃ CH₃ CH₃ H OCH₃ 104-106 Cl H H CH(CH₃)₂ H H OCH₃ 69-71Cl H H CH₃ H H H Cl H H H H H CN Cl H H H H H OCH₃ Cl H H OCH₃ H H H ClH H F H H OCH₃ Cl H H H F H OCH₃ Cl H H H H H SCH₃ Cl H H H H H CH₃ Cl HH H H H F Cl H H SCH₃ H H H Cl H H H OCH₃ H H Cl H H —(CH₂)₃— H OCH₃ ClF H H H H H F F H CH₃ H H OCH₃

EXAMPLE 4 Preparation of3-(6-Methoxy-m-tolyl)-5-nitro-1,2-benzisothiazole

Ammonium hydroxide (350 mL of a 30% solution, 270 mmol) is added to amixture of 2′-chloro-2-methoxy-5-methyl-5′-nitrobenzophenone (68.7 g,22.5 mmol) and sulfur (7.57 g, 23.6 mmol) in N,N-dimethylformamide. Theresultant reaction mixture is stirred at 80° C. for 19.5 hours, cooledto 40° C., treated with additional ammonium hydroxide (50 mL of a 30%solution), stirred at 80° C. for 25 hours, cooled, and poured onto ice.The resultant aqueous mixture is filtered to obtain the title product asa yellow solid (63.5 g, 93.9%) which is identified by NMR spectralanalyses.

Using essentially the same procedure, the following compounds areobtained:

W W₁ W₂ W₃ W₄ mp ° C. H H CH₃ H OCH₃ 201-203 H CH₃ CH₃ H OCH₃ 199-200 HCH₃ H H H 116.5-117.5 H H Cl H OCH₃ 229-231 H H H CH₃ OCH₃ 134-136 H H HH CN 187.5-189   H H H H OCH₃ 193-198 H H OCH₃ H H 201-203 H OCH₃ H H H174-175 H F H H OCH₃ 224-226 H C₂H₅ H H OCH₃   153-154.5 H H CH₃ H H188-189 H H N(CH₃)SO₂CH₃ H H H CH₃ Cl H OCH₃ 230-234 H I H H OCH₃ H HSCH₃ H H 177.5-178.5 H H OCH₃ H CH₃ 131-135 H H F H H 226-228 H H Cl H H217.5-219   H H F H OCH₃ 224-225 H H H H SCH₃ 114.5-115.5 H H CH₃ H OCH₃201-203 H OCH₃ H H OCH₃ 195-196 H H H H CH₃ 145-146 H H H H F 181-182 HH OCH₃ H OCH₃   171-172.5 H SCH₃ H H H   139-140.5 H CH₃ H CH₃ OCH₃ CH₃CH₃ CH₃ H OCH₃ H CH(CH₃)₂ H H OCH₃ H H CH₃ CH₃ OCH₃ H —(CH₂)₃— H OCH₃

EXAMPLE 5 Preparation of 3-Methyl-5-nitro-1,2-benzisothiazole

Ammonia (45 g, 2,642 mmol) is bubbled into methanol at −40° C. in asteel bomb. Sulfur (30.5 g, 95.0 mmol) and2′-chloro-5′-nitroacetophenone (19 g, 95.0 mmol) are then added. Thebomb is sealed and heated at about 90° C. overnight. After cooling, thereaction mixture is removed from the bomb and concentrated in vacuo toobtain a residue. The residue is diluted with methylene chloride, passedthrough a plug of silica gel and concentrated in vacuo to give the titleproduct as an orange solid (12.0 g) which is identified by NMR spectralanalyses.

Using essentially the same procedure, the following compounds areobtained:

EXAMPLE 6 Preparation of5-Amino-3-(6-methoxy-m-tolyl)-1,2-benzisothiazole

A mixture of 3-(6-methoxy-m-tolyl)-5-nitro-1,2-benzisothiazole (63.0 g,0.210 mol), 5% acetic acid (1.52 L, 1.21 mol) and ethyl acetate (975 mL)is heated to 65° C., treated portionwise with iron powder (58.6 g, 1.05mol), stirred at 65° C., and filtered through quartz filter paper. Thefiltrate phases are separated and the aqueous phase is extracted withethyl acetate. The organic phase and extracts are combined, washedsequentially with water and brine, dried over anhydrous magnesiumsulfate, and concentrated in vacuo to obtain the title product as anorange oil (55.7 g, 98.1%) which is identified by NMR spectral analyses.

Using essentially the same procedure, the following compounds areobtained:

X₅ R₄₀ mp ° C. H H H CN 118.5-120   H CH₃   112-113.5 H C₂H₅ H

179-181 H

90-91 F

H

  130-130.5 H

152-153 H

121.5-123   H

108.5-109.5 H

158.5-161   H

101.5-102.5 H

104-105 H

  191-192.5 H

H

H

128-129 H

H

64 H

108.5-109.5 H

133-134 H

114.5-115   H

  152-153.5 H

146-147 H

60-65 H

143-145 H

100-101 H

H

125-127 H

172-174 H

146-147 H

161-162 H

173-175 H

H

H

H

F CH₃ F

H CH₂CO₂C₂H₅ H C(CH₃)₂CO₂C₂H₅ H OCH₂CN H OCH₃ H OCH(CH₃)₂ H OCH₂CH═CH₂ HOCH₂C≡CH H OCH₂CO₂CH₃

EXAMPLE 7 Preparation of2-Chloro-2′-methoxy-5′-methyl-5-nitrobenzophenone, oxime

A mixture of 2-chloro-2′-methoxy-5′-methyl-5-nitro-benzophenone (90.0 g,0.294 mol) in ethanol is treated with a solution of hydroxylaminehydrochloride (102.3 g, 1.47 mol) in water, refluxed overnight, andpoured onto ice. The resultant aqueous mixture is filtered to obtain asolid. The solid is washed with water and dried in a hot vacuum ovenovernight to give the title product as a white solid (84.2 g) which isidentified by ¹H NMR spectral analysis.

Using essentially the same procedure, the following compounds areobtained:

X₅ W W₂ W₃ mp ° C. H OCH₃ H H 173-178 H H H H 143-145 H H OCH₃ H  191-192.5 H OCH₃ H F H H OCH₂CO₂CH₃ H 150-155 H OCH₃ H CH₃ 185.5-186.5F OCH₃ H CH₃ and

mp 165-167° C.

EXAMPLE 8 Preparation of 3-(6-Methoxy-m-tolyl)-5-nitro-1,2-benzisoxazole

A mixture of 2-chloro-2′-methoxy-5′-methyl-5-nitrobenzophenone, oxime(84.0 g, 0.262 mol) in ethanol is warmed to 65° C., treated with 150 mLof 10% potassium hydroxide solution over 25 minutes, heated to 78°C.over one hour, cooled, and poured onto ice. The resultant aqueousmixture is filtered to obtain a solid. The solid is washed with water,dried, recrystallized from N,N-dimethylformamide, washed sequentiallywith N,N-dimethyl-formamide and ethanol, and dried in a vacuum oven at80° C. to give the title product as a solid (mp 225-226° C.) which isidentified by ¹H NMR spectral analysis.

Using essentially the same procedure, the following compounds areobtained:

X₅ W W₁ W₂ mp ° C. H OCH₃ H H 170-171 H H H H 138-139 H H H OCH₃ 205-207F OCH₃ CH₃ H and

mp 84.5-86.5° C.

EXAMPLE 9 Preparation of 5-Amino-3-(6-methoxy-m-tolyl)-1,2-benzisoxazoleand 5-Amino-4-chloro-3-(6-methoxy-m-tolyl)-1,2-benzisoxazole

A mixture of 3-(6-methoxy-m-tolyl)-5-nitro-1,2-benzisoxazole (20.0 g,0.0703 mol) in acetic acid (380 mL) is warmed, treated with a warmsolution of tin(II) chloride dihydrate (47.4 g, 0.210 mol) inconcentrated hydrochloric acid (110 mL), refluxed for one hour, cooledto 10° C., and concentrated in vacuo to obtain a gum. The gum is addedto water with stirring to obtain a slurry. The slurry is treated with 80g of 50% sodium hydroxide solution, stirred at 60° C. to 80° C. over onehour, cooled, and decanted to obtain a residue. A mixture of the residuein ethanol is treated with potassium hydroxide (10 g ), heatedovernight, cooled to room temperature, neutralized with hydrochloricacid, and concentrated in vacuo to obtain a residue. The residue isdiluted with ethyl acetate and filtered. The filtrate is concentrated invacuo and chromatographed using silica gel and a 2% ethyl acetate inmethylene chloride solution to give the title products as semi-solidswhich are identified by elemental and mass spectral analyses.

Using essentially the same procedure, the following compounds areobtained:

X₅ R₄₁ H

H CH₃ H Cl H OCH₂CO₂CH₃ H OCH(CH₃)₂ H OCH(CH₃)CO₂CH₃ F OCH₂CO₂CH₃ H OCH₃

EXAMPLE 10 Preparation of m-Fluorophenyl acetate

A solution of 3-fluorophenol (100 g, 0.890 mol) in methylene chloride iscooled to 0° C. to 5° C., treated with pyridine (75.0 mL, 0.930 mol),stirred for several minutes, treated dropwise with acetyl chloride (66.0mL, 0.930 mol) while maintaining the reaction mixture temperature below17° C., stirred at ice-bath temperature for two hours, warmed to roomtemperature, and poured into an ice-water mixture. The organic phase isseparated, washed with brine, dried over anhydrous magnesium sulfate,and concentrated in vacuo to obtain the title product as a yellow oilwhich is identified by ¹H NMR spectral analysis.

EXAMPLE 11 Preparation of 4′-Fluoro-2′-hydroxyacetophenone

m-Fluorophenyl acetate (123 g, 0.798 mol) is cooled with an ice-bath,treated portionwise with aluminum chloride (150 g, 1.12 mol), stirred at190° C. for one hour, and cooled to obtain a solid. A mixture of ice,water and hydrochloric acid, and methylene chloride are added to thesolid. The resultant mixture is stirred for several minutes, and thephases are separated. The organic phase is washed sequentially withwater, saturated sodium hydrogen carbonate solution and brine, driedover anhydrous magnesium sulfate, and concentrated in vacuo to obtainthe title product (99.0 g) which is identified by ¹H NMR spectralanalysis.

EXAMPLE 12 Preparation of 4′-Fluoro-2′-hydroxyacetophenone, oxime

A mixture of 4′-fluoro-2′-hydroxyacetophenone (99.0 g, 0.640 mol),hydroxylamine hydrochloride (89.0 g, 1.28 mol), and sodium acetate (79.0g, 0.960 mol) in methanol is refluxed for one hour and poured into anice-water mixture. The resultant aqueous mixture is filtered to obtain asolid. The solid is dissolved in methylene chloride, and the resultantorganic solution is dried over anhydrous magnesium sulfate, concentratedin vacuo, diluted with hexanes, and filtered to give the title productas a solid (55.0 g, mp 112-114° C.) which is identified by ¹H NMRspectral analysis.

EXAMPLE 13 Preparation of 6-Fluoro-3-methyl-1,2-benzisoxazole

A mixture of 4′-fluoro-2′-hydroxyacetophenone, oxime (47.0 g, 0.278 mol)in tetrahydrofuran is heated to just under reflux, treated with asolution of 1,1′-carbonyl-diimidazole (55.0 g, 0.340 mol) andtriethylamine (39.0 g, 0.390 mol) in tetrahydrofuran, refluxed for onehour, cooled, concentrated in vacuo, and poured into an ice-watermixture. The resultant aqueous mixture is extracted with ether. Theorganic extracts are combined, washed sequentially with saturatedammonium chloride solution and brine, dried over anhydrous magnesiumsulfate, and concentrated in vacuo to obtain an oil. Columnchromatography of the oil using silica gel and a methylenechloride/hexanes solution (1:1) gives the title product as a yellow oilwhich is identified by ¹H NMR spectral analysis.

EXAMPLE 14 Preparation of 6-Fluoro-3-methyl-5-nitro-1,2-benzisoxazole

A mixture of 6-fluoro-3-methyl-1,2-benzisoxazole (23.5 g, 0.156 mol) inconcentrated sulfuric acid is cooled with an ice-bath, treated dropwisewith 90% nitric acid (8.50 mL) while maintaining the reaction mixturetemperature below 15° C., stirred for one hour at ice-bath temperature,treated with additional 90% nitric acid (5.80 mL), warmed to and stirredat room temperature overnight, and poured onto ice. The resultantaqueous mixture is filtered to obtain a solid. The solid is air-driedand dissolved in methylene chloride. The resultant organic solution isdried over anhydrous magnesium sulfate, diluted with hexanes, andfiltered to give the title product as a purple solid which is identifiedby ¹H NMR spectral analysis.

Using essentially the same procedure, the following compounds areobtained:

X₅ H Cl F

EXAMPLE 15 Preparation of Methyl [(5-nitro-1,2-benzisoxazol-3-yl)oxy]acetate

A mixture of 5-nitro-1,2-benzisoxazol-3-ol (3.90 g, 0.0220 mol) andpotassium carbonate (4.17 g, 0.0300 mol) in N,N-dimethylformamide isstirred for 30 minutes, treated with methyl bromoacetate (3.96 g, 0.0260mol), stirred overnight at room temperature, and poured into an acidicice-water mixture. The resultant aqueous mixture is extracted with ethylacetate. The organic extracts are combined, washed sequentially withwater and brine, dried over anhydrous magnesium sulfate, andconcentrated in vacuo to obtain a yellow oil. Column chromatography ofthe oil using silica gel and a (1:1) to (4:1) methylene chloride/hexanesgradient gives the title product as a white solid (2.80 g, mp 72-73.5°C.) which is identified by NMR spectral analyses.

Using essentially the same procedure, the following compounds areobtained:

X₅ R₄₁ mp ° C. H OCH(CH₃)₂ 81-83 H OCH₂CH═CH₂ 70-72 H OCH₃ 101.5-103  Cl OCH(CH₃)CO₂CH₃  98-100 F OCH₂CO₂CH₃ 104-106

EXAMPLE 16 Preparation of 3-Chloro-5-nitro-1,2-benzisoxazole

A mixture of 5-nitro-1,2-benzisoxazol-3-ol (4.00 g, 0.0220 mol) andphosphorus oxychloride (40.0 mL, 65.8 g, 0.429 mol) is placed in a glassbomb, heated at 150-155° C. for two hours, cooled overnight,concentrated in vacuo, diluted with methylene chloride, and brought toabout pH 8 with sodium hydrogen carbonate solution. The phases areseparated. The organic phase is washed sequentially with water andbrine, dried over anhydrous magnesium sulfate, and concentrated in vacuoto obtain a residue. Column chromatography of the residue using silicagel and a methylene chloride/hexanes solution (1:1) gives the titleproduct as an amber oil which is identified by NMR spectral analysis.

EXAMPLE 17 Preparation of 2-Chloro-2′-methoxy-5-nitrobenzophen-one

A solution of 2-bromoanisole (27.9 g, 145 mmol) in diethyl ether iscooled to −70° C., treated with butyllithium (64.0 mL, 160 mmol),stirred at −70° C. for one hour, treated with 0.5 M zinc chloride intetrahydrofuran solution (320 mL, 160 mmol), stirred for one hour at−70° C., warmed to about 0° C., and concentrated in vacuo to obtain ayellow-green oil. A solution of the oil in tetrahydrofuran is treatedsequentially with tetrakis(triphenylphosphine)palladium(O) (5.00 g, 4.35mmol) and a solution of 2-chloro-5-nitrobenzoyl chloride (35.0 g, 159mmol) in tetrahydrofuran, stirred for three days, and poured into 10%hydrochloric acid. The resultant aqueous mixture is extracted withmethylene chloride. The organic extracts are combined, washedsequentially with water and brine, dried over anhydrous magnesiumsulfate, and concentrated in vacuo to obtain a semi-solid. The solid istriturated with diethyl ether to give the title product as a yellowsolid which is identified by NMR spectral analyses.

Using essentially the same procedure, the following compounds areobtained:

W₁ W₂ W₃ W₄ mp ° C. H Cl H OCH₃ 96-99 H H CH₃ OCH₃ 71-74 F H H OCH₃ Cl HH OCH₃ 124-126 OCH₃ H H OCH₃ 71-73 H OCH₃ H OCH₃  98-100 H F H OCH₃ H HCH₃ H   65-66.5 H H SCH₃ H 87-88 H H H F 118-120 H H H CH₃   78-79.5 H HH SCH₃   123-124.5 H F H H H H OCH₃ H H H H OCH₃ H CH₃ CH₃ OCH₃

EXAMPLE 18 Preparation of 2-Chloro-2′-methoxy-5-nitrobenzhydrol

A solution of 2-bromoanisole (50.0 g, 0.267 mol) in ether is addedportionwise to a mixture of magnesium (7.10 g, 0.293 mol) in ether.After the addition is complete, the reaction mixture is heated at refluxfor one hour, diluted with ether, cooled to 0° C., treated with asolution of 2-chloro-5-nitrobenzaldehyde (39.0 g, 0.210 mol) intetrahydrofuran, warmed to room temperature, and diluted with anice-water mixture. After acidifying the aqueous mixture withhydrochloric acid (pH2-pH3), the organic phase is separated and theaqueous phase is extracted with ether. The organic extracts arecombined, washed sequentially with 10% sodium hydrogen carbonatesolution and brine, dried over anhydrous sodium sulfate, andconcentrated in vacuo to give the title product as a brown gum.

Using essentially the same procedure, the following compounds areobtained:

W W₃ W₄ OCH₃ H OCH₃ CH₃ H OCH₃ F H OCH₃ H OCH₃ H

EXAMPLE 19 Preparation of 2-Chloro-2′-methoxy-5-nitrobenzo-phenone

A solution of chromium(VI) oxide (91.0 g, 0.919 mol) in a water/aceticacid solution (1:4) is added portionwise to2-chloro-2′-methoxy-5-nitrobenzhydrol (64.2 g, 0.219 mol) whilemaintaining the reaction mixture temperature at 25° C. to 35° C. Thereaction mixture is then stirred at 25° C. to 35° C. for one hour,cooled, diluted with water, and concentrated in vacuo to obtain aresidue. The residue is diluted with water, and extracted with methylenechloride. The organic extracts are combined, dried over anhydrous sodiumsulfate, mixed with silica gel (10 g), and filtered. The filtrate isconcentrated in vacuo to obtain an oil. A solution of the oil in amethanol/water solution is decolorized with charcoal and concentrated invacuo to yield a residue. Column chromatography of the residue usingsilica gel and methylene chloride/hexanes solutions gives the titleproduct as a white solid.

Using essentially the same procedure, the following compounds areobtained:

W₁ W₃ W₄ mp ° C. OCH₃ H OCH₃ CH₃ H OCH₃ 109-111 F H OCH₃ 94-95 H OCH₃ H79-81

EXAMPLE 20 Preparation of 2-Chloro-4-fluoro-5-nitrobenzoyl chloride

A mixture of 2-chloro-4-fluoro-5-nitrobenzoic acid (50.0 g, 0.228 mol)and N,N-dimethylformamide (5 drops) in 1,2-dichloroethane is treateddropwise with oxalyl chloride (30.8 mL, 0.353 mol), refluxed for 3hours, cooled, and concentrated in vacuo to obtain the title product asan orange solid which is identified by NMR spectral analyses.

Following essentially the same procedure, but using2,4-difluoro-5-nitrobenzoic acid, 2,4-difluoro-5-nitrobenzoyl chlorideis obtained as a brown oil.

EXAMPLE 21 Preparation of 2′-Chloro-4′-fluoro-5′-nitroacetophenone

A 2 M solution of methylzinc chloride in tetrahydrofuran (5.00 mL, 10.1mmol) is treated dropwise with a solution of2-chloro-4-fluoro-5-nitrobenzoyl chloride (2.00 g, 8.40 mmol) intetrahydrofuran, treated with tetrakis(triphenylphosphine)palladium(O)(0.400 g, 0.350 mmol), stirred at room temperature for one hour, andpoured into 3 N hydrochloric acid. The resultant aqueous mixture isextracted with ethyl acetate. The organic extracts are combined, washedsequentially with water and saturated sodium hydrogen carbonatesolution, dried over anhydrous magnesium sulfate, and concentrated invacuo to obtain a dark liquid. Flash column chromatography of the liquidusing silica gel and a methylene chloride in hexanes solution (6:4)gives the title product as an off-white solid (mp 66-68° C.) which isidentified by NMR spectral analyses.

EXAMPLE 22 Preparation of 6-Amino-3-methyl-5-nitro-1,2-benzisothiazole

A mixture of 2′-chloro-4′-fluoro-5′-nitroaceto-phenone (12.0 g, 0.0552mol), sulfur (1.77 g, 0.0552 mol), 30% ammonium hydroxide solution (100mL, 0.856 mol), and methanol is placed in a steel bomb, heated at 85° C.overnight, cooled, treated with additional sulfur (0.270 g) and 30%ammonium hydroxide solution (50 mL), heated at 85° C. overnight, cooled,filtered to remove solids, and extracted with ethyl acetate. The organicextracts are combined, washed sequentially with water and brine, driedover anhydrous magnesium sulfate, and concentrated in vacuo to obtain asolid. Flash column chromatography of the solid using silica gel, and0%, 1% and 2% diethyl ether in methylene chloride solutions gives thetitle product as an orange solid (4.19 g, mp 189-191° C.) which isidentified by NMR spectral analyses.

Using essentially the same procedure, the following compound isobtained:

EXAMPLE 23 Preparation of 6-Chloro-3-methyl-5-nitro-1,2-benzisothiazole

A mixture of tert-butyl nitrite (3.30 mL, 0.0278 mol) and copper(II)chloride (2.98 g, 0.0222 mol) in acetonitrile is heated to 65° C.,treated portionwise with 6-amino-3-methyl-5-nitro-1,2-benzisothiazole(3.88 g, 0.0185 mol), stirred at 65° C., cooled to room temperature, andpoured into 20% hydrochloric acid. The resultant aqueous mixture isextracted with ethyl acetate. The organic extracts are combined, washedwith 20% hydrochloric acid, dried over anhydrous magnesium sulfate, andconcentrated in vacuo to obtain a solid. Flash column chromatography ofthe solid using silica gel and methylene chloride/hexanes solutions (1:1and 3:1) gives the title product as a pale, yellow solid (2.54 g, mp156-158° C.) which is identified by NMR spectral analyses.

Using essentially the same procedure, the following compound isobtained:

EXAMPLE 24 Preparation of 6-Fluoro-3-methyl-5-nitro-1,2-benzisothiazole

A mixture of 6-chloro-3-methyl-5-nitro-1,2-benzisothiazole (2.25 g, 9.80mmol), potassium fluoride (2.85 g, 49.0 mmol), and 18-crown-6 (1.50 g,5.70 mmol) in acetonitrile is heated in a sealed tube for 29 days,filtered to remove solids, and partially concentrated in vacuo to obtaina liquid. The liquid is diluted with ethyl acetate, washed sequentiallywith water and brine, dried over anhydrous magnesium sulfate, andconcentrated in vacuo to obtain a dark, brown solid. Flash columnchromatography of the solid using silica gel and a 10% to 50% ethylacetate in hexanes gradient gives a yellow solid containing twocomponents. Flash column chromatography of the yellow solid using silicagel and a 50% to 70% methylene chloride in hexanes gradient gives thetitle product as a pale, yellow solid (0.870 g, mp 118-119° C.) which isidentified by NMR spectral analyses.

Using essentially the same procedure, the following compound isobtained:

EXAMPLE 25 Preparation of 2,2′-Dithiobis[5-nitrobenzoic acid]

A mixture of 2-chloro-5-nitrobenzoic acid (100 g, 0.496 mol) in ethanolis treated portionwise with potassium tert-butoxide (55.5 g, 0.495 mol),diluted with additional ethanol, heated to reflux, treated portionwisewith a solution prepared from sodium sulfide nonahydrate (60.0 g, 0.249mol), sulfur (8.80 g, 0.274 mol) and water, refluxed for two hours,cooled to room temperature, and treated with concentrated hydrochloricacid. The resultant acidic mixture is stirred for one hour and filteredto obtain a solid. The solid is washed with water and air-dried to givethe title product as a yellow powder which is identified by NMR spectralanalysis.

EXAMPLE 26 Preparation of 5-Nitro-1,2-benzisothiazol-3(2H)-one

A mixture of 2,2′-dithiobis[5-nitrobenzoic acid] (44.6 g, 0.113 mol) andthionyl chloride (49.0 mL, 0.670 mol) in methylene chloride is treatedwith N,N-dimethylformamide (0.800 mL), refluxed overnight, concentratedin vacuo, and diluted with 1,2-dichloroethane. The resultant organicsolution is treated with bromine (22.5 mL, 0.436 mol), stirred at roomtemperature for 20 minutes, refluxed for 3.5 hours, and concentrated invacuo to obtain a residue. A solution of the residue in1,2-dichloroethane is cooled with an ice-water bath, treated withconcentrated ammonia (112 mL) over 15 minutes, stirred at roomtemperature for 16 hours, cooled with an ice-water bath, and treatedwith concentrated hydrochloric acid. The resultant aqueous mixture isstirred at room temperature for one hour and filtered to obtain a solid.The solid is washed with water and air-dried to give the title productas a yellow solid which is identified by NMR spectral analysis.

EXAMPLE 27 Preparation of 3-Chloro-5-nitro-1,2-benzisothiazole

A mixture of 5-nitro-1,2-benzisothiazol-3(2H)-one (10.0 g, 0.0510 mol),phosphorus oxychloride (40.0 mL, 0.429 mol) and tributylamine (12.0 mL,0.050 mol) is heated at 103-115° C. for six hours, stirred at roomtemperature overnight, and poured into an ice-water mixture. Theresultant aqueous mixture is extracted with methylene chloride. Thecombined organic extracts are washed sequentially with water andsaturated sodium hydrogen carbonate solution, dried over anhydroussodium sulfate, and concentrated in vacuo to obtain a gum. Columnchromatography of the gum using silica gel and methylene chloride givesthe title product as an orange-yellow solid which is identified by NMRspectral analysis.

EXAMPLE 28 Preparation of Ethylα-cyano-5-nitro-1,2-benziso-thiazole-3-acetate

A sodium ethoxide solution (previously prepared from ethanol and sodium(1.00 g, 0.0430 mol)) is cooled with an ice-acetone bath, treatedportionwise with ethyl cyanoacetate (4.51 g, 0.0398 mol), stirred atroom temperature for 30 minutes, treated with3-chloro-5-nitro-1,2-benzisothiazole (4.27 g, 0.0199 mol), stirred atroom temperature overnight, cooled to 0° C., and treated dropwise with10% hydrochloric acid (15.0 mL). The resultant aqueous mixture isstirred at room temperature for one hour and filtered to obtain a solid.The solid is washed with ethanol and air-dried to give the title productas a yellow solid which is identified by NMR spectral analysis.

EXAMPLE 29 Preparation of Ethyl 5-nitro-1,2-benzisothiazole-3-acetate

Ethyl α-cyano-5-nitro-1,2-benzisothiazole-3-acetate (6.67 g, 0.0229 mol)is added to a solution of acetyl chloride (67.0 mL) in ethanol. Thereaction mixture is refluxed overnight, cooled, and filtered to removesolids. The resultant filtrate is concentrated in vacuo to obtain abrown semi-solid. A mixture of the semi-solid in diethyl ether isstirred for two hours and filtered to obtain a solid. The solid iswashed with diethyl ether and air-dried to give the title product asyellow crystals (1.04 g, mp 91-92° C.).

EXAMPLE 30 Preparation of 5-Nitro-1,2-benzisothiazole-3-acetonitrile

A mixture of ethyl 5-nitro-1,2-benzisothiazole-3-acetate (5.00 g, 17.2mmol), water (1.00 mL), and methyl sulfoxide (35.0 mL) is stirred at107° C. for 24 hours, stirred at room temperature for two days, andpoured into an ice-water mixture. The resultant aqueous mixture isstirred for two hours and filtered to obtain a solid. The solid iswashed with water and air-dried to give the title product as a tansolid.

EXAMPLE 31 Preparation ofα,α-Dimethyl-5-nitro-1,2-benziso-thiazole-3-acetonitrile

A mixture of 5-nitro-1,2-benzisothiazole-3-acetonitrile (1.29 g, 5.89mmol) in N,N-dimethylformamide is cooled to −9° C., treated with sodiumhydride (1.00 g of a 60% dispersion in oil), stirred at −3° C. for 20minutes, treated with iodomethane (5.00 mL), stirred at room temperaturefor four hours, and poured onto ice. The resultant aqueous mixture istreated with 10% hydrochloric acid and extracted with methylenechloride. The combined organic extracts are washed sequentially withwater, saturated sodium hydrogen carbonate solution and water, driedover anhydrous sodium sulfate, and concentrated in vacuo to obtain asolid. Column chromatography of the solid using silica gel and methylenechloride gives the title product as a yellow solid which is identifiedby NMR spectral analysis.

EXAMPLE 32 Preparation of Ethylα,α-dimethyl-5-nitro-1,2-benzisothiazole-3-acetate

A mixture of α,α-dimethyl-5-nitro-1,2-benzisothiazole-3-acetonitrile(0.913 g, 3.69 mmol), water (0.450 mL), concentrated sulfuric acid (4.55mL) and ethanol (9.10 mL) is refluxed for one hour, cooled, and pouredonto ice. The resultant aqueous mixture is neutralized with saturatedsodium bicarbonate solution and extracted with methylene chloride. Theorganic extract is washed with water, dried over anhydrous sodiumsulfate, and concentrated in vacuo to obtain a solid. Columnchromatography of the solid using silica gel and methylene chloridegives the title product as pale yellow crystals. spectral analysis.

EXAMPLE 33 Preparation of 5-Amino-3-chloro-1,2-benzisothiazole

A solution of 3-chloro-5-nitro-1,2-benzisothiazole (2.00 g) in tolueneis treated with iron powder (8.40 g, 325 mesh) and concentratedhydrochloric acid (8 drops), heated to reflux, treated dropwise withwater (8.00 mL), refluxed for 35 minutes, cooled to room temperature,and filtered through diatomaceous earth. The resultant filtrate isconcentrated in vacuo to obtain a residue. Flash column chromatographyof the residue using silica gel and an ethyl acetate/hexanes solution(1:1) gives the title product.

EXAMPLE 34 Preparation of[(5-Nitro-1,2-benzisothiazol-3-yl)-oxy]acetonitrile

A mixture of 5-nitro-1,2-benzisothiazol-3(2H)-one (17.5 g, 89.2 mmol) inN,N-dimethylformamide is treated with potassium carbonate (18.5 g, 134mmol), stirred at room temperature for 30 minutes, treated withbromoacetonitrile (16.0 g, 133 mmol), stirred at room temperatureovernight, and poured onto ice. The resultant aqueous mixture isacidified to pH 3 with hydrochloric acid and extracted with ethylacetate. The combined organic extracts are washed sequentially withwater and brine, dried over anhydrous magnesium sulfate, andconcentrated in vacuo to obtain a solid. Column chromatography of thesolid using silica gel and methylene chloride gives the title product asa yellow solid (15.0 g, mp 123-124.5° C.).

Using essentially the same procedure, the following compounds areobtained:

R₄₀ mp ° C. OCH₃ 108-109 OCH(CH₃)₂ OCH₂CH═CH₂ OCH₂C≡CH 115-117OCH₂CO₂CH₃

EXAMPLE 35 Preparation of 5-Nitro-1,2-benzisothiazole

To a mixture of ammonium hydroxide (1000 ml) and N,N-dimethylformamideis added 2-chloro-5-nitrobenzaldehyde (300 g, 1.62 mol) and sulfur (54.4g, 1.70 mol). The mixture is heated slowly to and stirred at 90° C. forone hour, cooled to room temperature, poured onto ice, and diluted withwater. Filtration affords the title compound as a yellow solid (277.1 g,94.9%).

Using essentially the same procedure, but using2′-chloro-5′-nitro-2-methyl-2-carboethoxypropiophenone, ethylα,α-dimethyl-5-nitro-1,2-benzisothiazole-3-acetate is obtained as asolid (mp 75-77° C.).

EXAMPLE 36 Preparation of 3-Chloro-5-nitro-1,2-benzisothiazole

A suspension of 5-nitro-1,2-benzisothiazole (271 g, 1.50 mol) in aceticacid is heated to 80° C. to form a solution. The heating source isremoved and chlorine gas is added continuously over six hours at 70-80°C. until saturation of the mixture occurs. The mixture is cooled to roomtemperature and stirred overnight. Filtration affords the title compoundas a yellow crystalline solid (237 g, 73.6%) which is identified by NMRspectral analysis.

EXAMPLE 37 Preparation of 2′-Chloro-2-methyl-2-carboethoxy propiophenone

A mixture of 2-chlorobenzoyl chloride (52.2 g, 0.298 mol), ethyl2-bromoisobutyrate (58.2 g, 0.298 mol) and ether is added in portions tozinc foil (19.5 g, 0.298 mol) and the resultant mixture stirred atreflux for three hours and overnight at room temperature. The mixture ispoured into cold, dilute sulfuric acid and the organic layer is washedwith saturated sodium bicarbonate and brine, dried over anhydrousmagnesium sulfate and concentrated in vacuo to a yellow oil. The oil ischromatographed on silica gel with hexanes:ethyl acetate to afford thetitle compound as a colorless oil (41.8 g, 55.1%).

EXAMPLE 38 Preparation of2′-Chloro-5′-nitro-2-methyl-2-carboethoxypropiophenone

To concentrated sulfuric acid (15.0 ml) at 5° C. is added2′-chloro-2-methyl-2-carboethoxypropiophenone (4.00 g, 0.01570 mol)followed by dropwise addition of concentrated nitric acid (90%, 0.740ml, 0.0204 mol). After stirring 5 minutes, the mixture is poured ontoice and extracted with ethyl acetate. The organic layers are washed withsaturated sodium bicarbonate and brine, dried over anhydrous magnesiumsulfate, filtered and concentrated in vacuo to afford the title compoundas a yellow oil (3.90 g, 83.0%) which is identified by NMR spectralanalysis.

EXAMPLE 39 Preparation of 1-Benzothiophen-2,3-dione

To a solution of thiophenol (100 g, 0.907 mol) in ether is addeddropwise a solution of oxalyl chloride (175 g, 1.38 mol) in ether. Themixture is stirred two hours at reflux and concentrated in vacuo. Theresidue is taken up in methylene chloride and cooled to 0° C. Aluminumchloride (145 g, 1.09 mol) is added in portions such that thetemperature does not exceed 25° C. The resultant mixture is stirred 30minutes at reflux, cooled to room temperature and poured into ice waterwith stirring. The organic layer is washed with saturated sodiumbicarbonate, water and brine, dried over anhydrous magnesium sulfate,filtered and concentrated in vacuo to an orange solid which isrecrystallized from methylene chloride:hexanes to afford the titlecompound (102 g, 69.0%) which is identified by NMR spectral analysis.

EXAMPLE 40 Preparation of 1,2-Benzisothiazole-3-carboxamide

To ammonium hydroxide (1.78 l) is added 1-benzothiophen-2,3-dione (87.0g, 0.530 mol) at 5-10° C., followed by hydrogen peroxide (30% aqueous,178 ml). The resultant mixture is filtered to obtain a yellow solidwhich is dried (77.0 g, 81.7%) and identified as the title compound byNMR and IR spectral analysis.

EXAMPLE 41 Preparation of 3-Cyano-5-nitro-1,2-benzisothiazole

A solution of 1,2-benzisothiazole-3-carboxamide (12.0 g, 0.0674 mol) inconcentrated sulfuric acid at 0-5° C. is treated dropwise with nitricacid (90%, 4.12 ml) such that the temperature does not exceed 10° C.,stirred one hour at 5° C., and poured into ice water with vigorousstirring. The resultant suspension is filtered to obtain a solid. Thesolid is dried and recrystallized from acetonitrile to afford a whitesolid (10.0 g) which is treated with phosphorus oxychloride (60.0 ml).The resultant mixture is stirred at 90-100° C. for 90 minutes, cooled toroom temperature, slowly poured into ice water with stirring, andfiltered to obtain a solid. Recrystallization of the solid frommethylene chloride:hexanes gives the title compound as an orange solid(8.00 g, 87.9%, mp 168-170° C.) which is identified by NMR and IRspectral analyses.

EXAMPLE 42 Preparation of3-(6-Methoxy-m-tolyl)-6-amino-5-nitro-1,2-benzisothiazole

Ammonium hydroxide (330 ml) is added to a suspension of2′,4′-difluoro-2-methoxy-5-methyl-5′-nitrobenzophenone (60.0 g, 0.186mol), sulfur (6.25 g, 0.195 mol) and N,N-dimethylformamide on an icebath. The resultant mixture is allowed to warm to 35° C., heatedgradually to 81° C. over a two hour period, cooled to room temperature,and poured into water. The resultant solid is taken up in ethyl acetateand N,N-dimethylformamide, and washed with water. The organic layer isconcentrated in vacuo to afford the title compound which is identifiedby NMR spectral analysis.

EXAMPLE 43 Preparation of3-(6-Methoxy-m-tolyl)-6-chloro-5-nitro-1,2-benzisothiazole

A mixture of tert-butyl nitrite (5.90 g, 0.0571 mol), copper chloride(6.20 g, 0.0457 mol) and acetonitrile is heated to 65-75° C., treatedwith 3-(6-methoxy-m-tolyl)-6-amino-5-nitro-1,2-benzisothiazole (12.0 g,0.0381 mol) over 10 minutes, stirred for two hours at 67-75° C., treatedwith tert-butyl nitrite (1.50 ml) and copper chloride (1.00 g), stirred40 minutes at 67-75° C., cooled to room temperature, and diluted withethyl acetate. The organic layer is washed with 10% hydrochloric acidand filtered. The filtrate is washed with water and concentrated invacuo to afford the title compound as a solid (10.6 g, 83.1%) which isidentified by NMR and IR spectral analyses.

EXAMPLE 44 Preparation of3-(6-Methoxy-m-tolyl)-6-fluoro-5-nitro-1,2-benzisothiazole

A mixture of 3-(6-methoxy-m-tolyl)-6-chloro-5-nitro-1,2-benzisothiazole(7.30 g, 0.0218 mol), potassium fluoride (6.33 g, 0.109 mol) 18-crown-6(2.31 g, 0.0872 mol) and sulfolane is stirred 19 hours at 154° C.,cooled to room temperature, and poured into ice water. The resultantsolid is filtered and chromatographed on silica gel with methylenechloride to afford a solid which is recrystallized from acetonitrile toafford a tan powder. The powder is recrystallized from ethyl acetate togive the title compound as a tan solid (2.09 g, 29.9%) which isidentified by NMR spectral analysis.

EXAMPLE 45 Preparation of5-Amino-4-bromo-6-fluoro-3-methyl-1,2-benzisothiazole

To a solution of 5-amino-6-fluoro-3-methyl-1,2-benzisothiazole (0.600 g,0.00329 mol) in 1,2-dichloroethane is added N-bromosuccinimide (0.586 g,0.00329 mol) followed by 1,1′-azobis(cyclohexanecarbo-nitrile) (0.0200g). The mixture is stirred two hours at 70° C., additionalN-bromosuccinimide (0.240 g, 0.00135 mol) is added, and the mixture isstirred 40 minutes at 70° C. The mixture is then cooled to roomtemperature, filtered and concentrated in vacuo to obtain a residue. Theresidue is chromatographed on silica gel to give the title compound(0.870 g, 100w) which is identified by NMR spectral analysis.

What is claimed is:
 1. A process for the preparation of a6-(perfluoroalkyl)uracil compound having the structural formula I

wherein n is an integer of 1, 2, 3, 4, 5 or 6; Y is hydrogen orC₁-C₆alkyl; and Q is a C₁-C₆alkyl group or an optionally substitutedphenyl, benzyl, heteroaryl or methyleneheteroaryl group, which processcomprises (a) reacting a urea compound having the structural formula II

wherein Z and Z₁ are each independently C₁-C₈alkyl or Z and Z₁ may betaken together with the atom to which they are attached to form a 4- to7-membered ring wherein ZZ₁ is represented by —(CH₂)₂O (CH₂)₂— or—(CH₂)_(m)— where m is an integer of 3, 4, 5 or 6; Z₂ is C₁-C₆alkyl orbenzyl optionally substituted on the phenyl ring with any combination offrom one to three halogen, C₁-C₄alkyl or C₁-C₄haloalkyl groups; and n isas described above, with an amine compound having the structural formulaIII

wherein Q is as described above in the presence of an acid or base toform the 6-(perfluoroalkyl)uracil compound of formula I wherein Y ishydrogen; and (b) optionally alkylating the formula I compound wherein Yis hydrogen, to form a formula I compound wherein Y is C₁-C₆ alkyl.
 2. Aprocess according to claim 1 wherein the double bond in the formula IIcompound is predominately in the (Z)— configuration.
 3. A processaccording to claim 1 wherein the reaction in step (a) is carried out inthe presence of an acid.
 4. A process according to claim 3 wherein saidacid is selected from the group consisting of a C₁-C₆ alkanoic acid,hydrochloric acid, sulfuric acid and phosphoric acid.
 5. A processaccording to claim 3 wherein said acid is acetic acid.
 6. A processaccording to claim 1 wherein the base is selected from the groupconsisting of a tri(C₁-C₆alkyl)amine, a heterocyclic tertiary amine andan alkali metal C₁-C₆alkoxide.
 7. A process according to claim 6 whereinthe base is selected from the group consisting of1,8-diazabicyclo[5.4.0]undec-7-ene and1,5-diazabicyclo-[4.3.0]non-5-ene.
 8. A process according to claim 1wherein the urea compound is reacted with the amine compound and in thepresence of a solvent.
 9. A process according to claim 8 wherein saidsolvent is selected from the group consisting of a carboxylic acidamide, a dialkyl sulfoxide, an aromatic hydrocarbon, a halogenatedaromatic hydrocarbon, an aliphatic hydrocarbon, a halogenated aliphatichydrocarbon, an alcohol, an alkanoic acid, a ketone, an ether, a nitrileand water and mixtures thereof.
 10. A process according to claim 1wherein the urea compound is reacted with the amine compound at atemperature of about 20° C. to 150° C.
 11. A process according to claim1 wherein step (b) comprises reacting the formula I compound wherein Yis hydrogen with an alkyl halide having the structural formula IV or adialkylsulfate ester having the structural formula V

wherein X is chlorine, bromine or iodine, and Y is C₁-C₆alkyl, in thepresence of a base.
 12. A process according to claim 1 wherein n is 1; Yis hydrogen or C₁-C₄alkyl; Q is

G is CH₂ or a bond; G₁ is CX₅ or N; G₂ is CX₄ or N; X₁ is hydrogen,halogen or a C₁-C₆alkyl group optionally substituted with one epoxygroup, X₂ is hydrogen, halogen NRR₁, CO₂R₂, C(O)R₃, OR₄, SO₂R₅,SO₂NR₆R₇, C(R₈) (OR₉)₂,C(R₁₀)═NOR₁₁, C(R₁₂)═C(R₁₃)—C(OR₁₄)═NOR₁₅,CH₂O—NCO₂R₁₆,  1,3-dioxolane optionally substituted with one C₁-C₆alkoxygroup or one or two C₁-C₄alkyl groups,  1,3-dioxolinone optionallysubstituted with one C₁-C₆alkoxy group or one or two C₁-C₄alkyl groups,or  C₁-C₄alkyl optionally substituted with one CO₂R₂ group and onehalogen atom, and X₃ is hydrogen, halogen, C₁-C₄haloalkyl, CO₂R₁₇,cyano, C₁-C₄haloalkoxy, OR₁₈ or C₁-C₄alkyl, or when X₁ and X₂ are takentogether with the atoms to which they are attached, they may form afive- or six-membered ring wherein X₁X₂ or X₂X₁ is represented by: —OC(R₂₀) (R₂₁)O—, —CH₂S(O)_(P)N(R₂₂)—, —SC(R₂₃)═N—, —CH═CH—CH (R₁₁)O—,—OC(O)N—, —SC(R₂₄)═N—, —ON(R₂₅)C(O)—, —OC(CO₂R₂₆)═C(R₂₇)—,—NC(R₂₈)═C(SR₂₉)—, —CH═C(CO₂R₃₀)O—, —CH₂CH(R₃₁)O— or —OC(R₃₂)(R₃₃)C(O)—,or when X₂ and X₃ are taken together with the atoms to which they areattached, they may form a five- or six-membered ring wherein X₂X₃ orX₃X₂ is represented by:  —NC(R₃₄)═NC(S)—, —N(R₃₅)N═C(R₃₆)—,—N(R₃₇)C(R₃₈)═N—, —N(R₃₈)C(O)CH₂O—, —N(R₃₉)C(O)CH═CH—, —S—N═C(R₄₀)—,—O—N═C(R₄₁)—, —N═N—N(R₄₂)—, —C(R₄₃) (R₄₄)C(O)N(R₄₅)— or—N(R₄₆)C(O)C(R₄₇) (R₄₈)—; X₄ is hydrogen, halogen or OR₁₉; X₅ ishydrogen or halogen; R, R₅₆, R₆₄, R₆₉, R₇₀, R₇₇ and R₉₁ are eachindependently hydrogen, SO₂R₄₉, C₁-C₄alkyl, C₃-C₇cycloalkyl,C₃-C₆alkenyl, C₃-C₆alkynyl, phenyl or benzyl; R₁ is hydrogen, SO₂R₅₀,C(O)R₅₁, amino or C₁-C₄alkyl optionally substituted with CO₂R₅₂ orC(O)R₅₃; R₂, R₁₆, R₁₇, R₂₆, R₃₀, R₆₈, R₇₅, R₇₆, R₈₂ and R₈₈ are eachindependently hydrogen, C₁-C₈haloalkyl, C₃-C₈alkenyl, C₃-C₆alkynyl,phenyl, benzyl, furfuryl, pyridyl, thienyl, C₁-C₈alkyl optionallysubstituted with CO₂R₅₄, morpholine or C(O)R₅₅, or  an alkali metal, analkaline earth metal, ammonium or organic ammonium cation; R₃, R₆₆, R₆₇,R₈₁, R₈₅ and R₈₉ are each independently hydrogen, C₁-C₆alkyl,C₃-C₆alkenyl, C₃-C₆alkynyl, NR₅₆R₅₇, phenyl or benzyl; R₄, R₁₈, R₁₉ andR₆₅ are each independently hydrogen, C₁-C₆alkyl, C₃-C₆alkenyl,C₃-C₆alkynyl, C₁-C₄haloalkyl, C(O)R₅₈, C(S)R₅₉ or benzyl; R₅ and R₇₂ areeach independently C₁-C₆alkyl, C₁-C₆haloalkyl, NR₆₀R₆₁, imidazole orindazole; R₆, R₁₁, R₁₂, R₁₄, R₁₅, R₂₀, R₂₁, R₂₂, R₂₅, R₂₈, R₂₉, R₃₁,R₃₂, R₃₃, R₃₅, R₄₅, R₄₆, R₆₃ and R₈₀ are each independently hydrogen orC₁-C₄alkyl; R₇ is hydrogen, C₃-C₆alkenyl, C₃-C₆alkynyl, benzyl, orC₁-C₄alkyl optionally substituted with cyano or C(O)R₆₂; R₈ and R₂₇ areeach independently hydrogen, C₁-C₄alkyl or C₁-C₄alkoxy; R₉ and R₉₀ areeach independently C₁-C₆alkyl; R₁₀ is hydrogen, C₁-C₆alkyl, phenyl orbenzyl; R₁₃, R₂₄ and R₃₆ are each independently hydrogen, C₁-C₆alkyl orhalogen; R₂₃ is hydrogen or NR₆₃R₆₄; R₃₄ is hydrogen, C₁-C₄alkyl orC₁-C₄haloalkyl; R₃₇ is hydrogen, C₁-C₄alkyl or C₂-C₈alkoxyalkyl; R₃₈ andR₃₉ are each independently hydrogen, C₁-C₄alkyl, C₁-C₄haloalkyl,C₃-C₆alkenyl or C₃-C₆alkynyl; R₄₀, R₄₁ and R₄₂ are each independentlyhydrogen, halogen, cyano, OR₆₅, C(O)R₆₆, C(S)R₆₇, CO₂R₆₈, C(═NOR₆₉),  aC₁-C₈alkyl, C₃-C₇cycloalkyl, C₂-C₈alkenyl or C₂-C₈alkynyl group, whereineach group is optionally substituted with any combination of one to sixhalogen atoms, one to three C₁-C₁₀-alkoxy groups, one or twoC₁-C₆haloalkoxy groups, one or two NR₇₀R₇₁ groups, one or twoS(O)_(q)R₇₂ groups, one or two cyano groups, one or two C₃-C₇cycloalkylgroups, one OSO₂R₇₃ group, one or two C(O)R₇₄ groups, one or two CO₂R₇₅groups, one or two C(O)SR₇₆ groups, one or two C(O)NR₇₇R₇₈ groups, oneto three OR₇₉ groups, one or two P(O) (OR₈₀)₂ groups, one 1,3-dioxolaneoptionally substituted with one to three C₁-C₄alkyl groups, or one1,3-dioxane optionally substituted with one to three C₁-C₄alkyl groups,or  phenyl or benzyl optionally substituted with any combination of oneto three halogen atoms, one to three C₁-C₆alkyl groups, one to threeC₁-C₆alkoxy groups, one C₃-C₇cycloalkyl group, one C₁-C₄haloalkyl group,one C₁-C₄alkylthio group, one cyano group, one nitro group, one C(O)R₈₁group, one CO₂R₈₂ group, one OR₈₃ group, one SR₈₄ group, oneC₁-C₆alkoxymethyl group, one hydroxymethyl group, oneC₃-C₈alkenyloxymethyl group, or one C₁-C₈haloalkoxymethyl group; R₄₃,R₄₄, R₄₇ and R₄₈ are each independently hydrogen, C₁-C₄alkyl,C₁-C₄haloalkyl, C₃-C₆alkenyl, C₃-C₆alkynyl or C₃-C₇cycloalkyl, or R₄₃and R₄₄ or R₄₇ and R₄₈ may be taken together with the atom to which theyare attached to form a C₃-C₇cycloalkyl group; R₄₉, R₅₀ and R₈₆ are eachindependently C₁-C₆alkyl, NR₉₃R₉₄, C₁-C₄haloalkyl, C₃-C₆alkenyl,C₃-C₆alkynyl or benzyl; R₅₁, R₅₂, R₅₃, R₅₄, R₅₅, R₅₇, R₅₈, R₅₉, R₆₀,R₆₁, R₆₂, R₇₁, R₇₃, R₇₄, R₇₈, R₈₇ and R₉₂ are each independentlyhydrogen, C₁-C₆alkyl, C₃-C₇cycloalkyl, C₁-C₆haloalkyl, C₃-C₆alkenyl,C₃-C₆alkynyl, phenyl or benzyl; R₇₉, R₈₃ and R₈₄ are each independentlyhydrogen, C(O)R₈₅, SO₂R₈₆, C₁-C₆haloalkyl, C₂-C₆alkenyl,C₅-C₈cycloalkenyl, C₂-C₆alkynyl, phenyl, benzyl, or C₁-C₁₀alkyloptionally substituted with one hydroxyl, benzyloxy, OC(O)R₈₇,C₁-C₆alkoxy, CO₂R₈₈, C(O) R₈₉, C(OR₉₀)₂, C(O)NR₉₁R₉₂ or cyano group; R₉₃and R₉₄ are each independently hydrogen, C₁-C₄haloalkyl, C₂-C₆alkenyl,C₃-C₈cycloalkyl, C₁-C₈alkyl optionally substituted with one or twoC₁-C₄alkoxy groups or one cyanoalkyl group, or  benzyl or phenyloptionally substituted with any combination of one to three halogenatoms, one to three C₁-C₄alkyl groups, one to three C₁-C₄haloalkylgroups, one to three C₁-C₄alkoxy groups, one to three C₁-C₄haloalkoxygroups, one cyano group or one nitro group, and  when R₉₃ and R₉₄ aretaken together with the atom to which they are attached, they form a 5-to 12-membered monocyclic or fused bicyclic, heterocyclic ringoptionally substituted with one or more groups independently selectedfrom halogen, cyano, nitro, amino, hydroxyl, C₁-C₄alkyl, C₁-C₄haloalkyl,C₁-C₄alkoxy, C₁-C₄haloalkoxy and C₁-C₄haloalkylsulfonyl groups; p and qare each independently 0, 1 or 2; Z and Z₁ are each independentlyC₁-C₆alkyl; and Z₂ is C₁-C₄alkyl.
 13. A process according to claim 12wherein Y is hydrogen or methyl; X₁ is hydrogen, fluorine or C₁-C₃alkyloptionally substituted with one epoxy group; X₂ is hydrogen, halogenNRR₁, CO₂R₂, C(O)R₃, OR₄, SO₂R₅, SO₂NR₆R₇, C(R₈) (OR₉)₂, C(R₁₀)═NOR₁₁,C(R₁₂)═C(R₁₃)—C(OR₁₄)═NOR₁₅, CH₂O—NCO₂R₁₆,  1,3-dioxolane optionallysubstituted with one C₁-C₆alkoxy group or one or two C₁-C₄alkyl groups, 1,3-dioxolinone optionally substituted with one C₁-C₆alkoxy group orone or two C₁-C₄alkyl groups, or  C₁-C₄alkyl optionally substituted withone CO₂R₂ group and one halogen atom, and X₃ is hydrogen, halogen,C₁-C₄haloalkyl, CO₂R₁₇, cyano, C₁-C₄haloalkoxy, OR₁₈ or C₁-C₄alkyl, orwhen X₁ and X₂ are taken together with the atoms to which they areattached, they may form a five- or six-membered ring wherein X₁X₂ orX₂X₁ is represented by:  —OC(R₂₀) (R₂₁)O—, —CH₂S(O)_(P)N(R₂₂)—,—SC(R₂₃)═N—, —CH═CH—CH(R₁₁)O—, —OC(O)N—, —SC(R₂₄)═N—, —ON(R₂₅)C(O)—,—OC(CO₂R₂₆)═CH—, —NC(R₂₈)═C(SR₂₉)—, —CH═C(CO₂R₃₀)O—, —CH₂CH(R₃₁)O— or—OC(R₃₂) (R₃₃)C(O)—, or when X₂ and X₃ are taken together with the atomsto which they are attached, they may form a five- or six-membered ringwherein X₂X₃ or X₃X₂ is represented by:  —NC(R₃₄)═NC(S)—,—N(R₃₅)N═C(R₃₆)—, —N(R₃₇)C(R₃₈)═N—, —N(R₃₈)C(O)CH₂O—, —N(R₃₉)C(O)CH═CH—,—S—N═C(R₄₀)—, —O—N═C(R₄₁)—, —N═N—N(R₄₂)—, —C(R₄₃) (R₄₄)C(O)N(R₄₅)— or—N(R₄₆)C(O)C(R₄₇) (R₄₈)—; X₄ is hydrogen, halogen or OR₁₉; X₅ ishydrogen or halogen; R, R₆₄, R₆₉ and R₇₇ are each independentlyhydrogen, SO₂R₄₉ or C₁-C₄alkyl; R₁ is hydrogen, SO₂R₅₀, C(O)R₅₁, aminoor C₁-C₄alkyl optionally substituted with CO₂R₅₂ or C(O)R₅₃; R₂, R₁₆,R₁₇, R₂₆, R₃₀, R₆₈, R₇₅, R₇₆, R₈₂ and R₈₈ are each independentlyhydrogen, C₃-C₆alkenyl or C₁-C₄alkyl optionally substituted with CO₂R₅₄,morpholine or C(O)R₅₅; R₃, R₆₆, R₆₇, R₈₅ and R₈₉ are each independentlyhydrogen, C₁-C₄alkyl or NR₅₆R₅₇; R₄, R₁₈ and R₁₉ are each independentlyhydrogen, C₁-C₄alkyl, C₁-C₄haloalkyl, C(O)R₅₈, C₃-C₄alkenyl orC₃-C₄alkynyl; R₅₆ is SO₂R₄₉; R₅₇ is hydrogen or C₁-C₄alkyl; R₅ and R₇₂are each independently NR₆₀R₆₁ or indazole; R₆, R₁₁, R₁₂, R₁₄, R₁₅, R₂₀,R₂₁, R₂₂, R₂₅, R₂₈, R₂₉, R₃₁, R₃₂, R₃₃, R₃₅, R₄₅, R₄₆ and R₈₀ are eachindependently hydrogen or methyl; R₇ is C₁-C₄alkyl optionallysubstituted with cyano or C(O)R₆₂; R₈ is hydrogen or C₁-C₄alkoxy; R₉ andR₉₀ are each independently C₁-C₄alkyl; R₁₀ is hydrogen or C₁-C₃alkyl;R₁₃, R₂₄ and R₃₆ are each independently hydrogen or chlorine; R₂₃ isNR₆₃R₆₄; R₃₄ is C₁-C₃haloalkyl; R₃₇ is C₂-C₄alkoxyalkyl; R₃₈ and R₃₉ areeach independently C₁-C₃haloalkyl, C₁-C₃alkyl or propargyl; R₄₀, R₄₁ andR₄₂ are each independently hydrogen, C(O)R₆₆, C(S)R₆₇, CO₂R₆₈,C(═NOR₆₉),  C₁-C₃alkyl optionally substituted with any combination ofone or two halogen atoms, one or two C₁-C₃alkoxy groups, one or twoC₁-C₃haloalkoxy groups, one SO₂R₇₂ group, one or two cyano groups, oneC₃-C₅cycloalkyl group, one OSO₂R₇₃ group, one C(O)R₇₄ group, one CO₂R₇₅group, one C(O)SR₇₆ group, one C(O)NR₇₇R₇₈ group, one to two OR₇₉groups, one P(O) (OR₈₀)₂ group, one 1,3-dioxolane group or one1,3-dioxane group, or  phenyl optionally substituted with anycombination of one halogen atom, one or two methyl groups, one methoxygroup, one halomethyl group or one OR₈₃ group; R₄₃, R₄₄, R₄₇ and R₄₈ areeach independently hydrogen or methyl, or R₄₃ and R₄₄ or R₄₇ and R₄₈ maybe taken together with the atom to which they are attached to form acyclopropyl group; R₄₉, R₅₀, and R₈₆ are each independently C₁-C₄alkylor NR₉₃R₉₄; R₅₁, R₅₂, R₅₃, R₅₄, R₅₅, R₅₈, R₆₀, R₆₁, R₆₂, R₇₃, R₇₄, R₇₈and R₈₇ are  each independently hydrogen, C₁-C₄alkyl or C₁-C₄haloalkyl;R₇₉ and R₈₃ are each independently hydrogen, C(O)R₈₅, SO₂R₈₆,C₁-C₄haloalkyl, C₃-C₄alkenyl or C₁-C₃alkyl substituted with oneOC(O)R₈₇, CO₂R₈₈, C(O)R₈₉, C(OR₉₀)₂ or cyano group; R₉₃ and R₉₄ are eachindependently hydrogen or C₁-C₈alkyl; p is 0, 1 or 2; Z and Z₁ are thesame and represent methyl or ethyl; and Z₂ is methyl or ethyl.
 14. Aprocess according to claim 1 for the preparation of a6-(trifluoromethyl)uracil compound having the structural formula VI

wherein Y is hydrogen or methyl; X₅ is hydrogen or halogen; R₄₀ ishydrogen, C(O)R₆₆, C(S)R₆₇, CO₂R₆₈,  C₁-C₃alkyl optionally substitutedwith any combination of one or two halogen atoms, one or two C₁-C₃alkoxygroups, one or two C₁-C₃haloalkoxy groups, one SO₂R₇₂ group, one or twocyano groups, one C₃-C₅cycloalkyl group, one OSO₂R₇₃ group, one or twoOR₇₉ groups, one P(O) (OR₈₀)₂ group, one 1,3-dioxolane group or one1,3-dioxane group, or  phenyl optionally substituted with anycombination of one halogen atom, one or two methyl groups, one methoxygroup, one halomethyl group or one OR₈₃ group; R₆₆, R₆₇, R₈₅ and R₈₉ areeach independently hydrogen, C₁-C₄alkyl or NR₅₆R₅₇; R₅₆ is SO₂R₄₉; R₅₇is hydrogen or C₁-C₄alkyl; R₄₉ and R₈₆ are each independently C₁-C₄alkylor NR₉₃R₉₄; R₉₃ and R₉₄ are each independently hydrogen or C₁-C₈alkyl;R₆₈ and R₈₈ are each independently hydrogen, C₃-C₆alkenyl or C₁-C₄alkyloptionally substituted with CO₂R₅₄, morpholine or C(O)R₅₅; R₅₄, R₅₅,R₆₀, R₆₁, R₇₃ and R₈₇ are each independently hydrogen, C₁-C₄alkyl orC₁-C₄haloalkyl; R₇₂ is NR₆₀R₆₁ or indazole; R₇₉ and R₈₃ are eachindependently hydrogen C(O)R₈₅, SO₂R₈₆, C₁-C₄haloalkyl, C₃-C₄alkenyl orC₁-C₃alkyl substituted with one OC(O)R₈₇, CO₂R₈₈, C(O) R₈₉, C(OR₉₀)₂ orcyano group; R₈₀ is hydrogen or methyl; and R₉₀ is C₁-C₄alkyl.